Antimony‐ and NSAID‐Induced Hepatotoxicity at the Molecular Crossroads: Redox, Inflammasome and Programmed Cell‐Death Networks as Therapeutic Targets for Natural Hepatoprotective Agents

ABSTRACT

Drug‐ and metal‐induced liver damage (DILI/MILI) continues to be a predominant cause of acute hepatic failure globally, with two clinically significant but mechanistically underexplored triggers being the metalloid antimony (Sb) and non‐steroidal anti‐inflammatory medications (NSAIDs). This review consolidates current molecular findings about the convergence of Sb(III)/Sb(V) species and NSAID reactive metabolites on a common hepatotoxic framework. Hepatic organic anion‐transporting polypeptides and multidrug‐resistance proteins regulate the sinusoidal uptake and canalicular efflux of both substances, while cytochrome P450 2C9/3A4/2E1‐mediated bioactivation of NSAIDs and thiol‐reactive Sb species produces reactive oxygen species (ROS), diminishes reduced glutathione (GSH) levels, disrupts mitochondrial membrane potential and initiates PERK‐eIF2α‐ATF4‐CHOP‐mediated endoplasmic reticulum stress. These insults target nuclear factor‐kappa B, mitogen‐activated protein kinase and NLRP3 inflammasome signalling, resulting in apoptotic, necroptotic, pyroptotic and ferroptotic hepatocyte death. We conduct a comprehensive assessment of the multi‐target hepatoprotective effects of polyphenols (curcumin, resveratrol, quercetin), flavonoids, terpenoids, alkaloids and extracts from medicinal plants, focusing on the activation of the Nrf2/Keap1/ARE antioxidant pathway, inhibition of NF‐κB and NLRP3, AMPK‐SIRT1‐PGC‐1α‐mediated mitochondrial biogenesis, PI3K/Akt cytoprotective signalling and PINK1/Parkin‐dependent mitophagy. We ultimately examine translational prospects, including omics‐derived hepatotoxicity biomarkers, network pharmacology, artificial intelligence‐facilitated natural product discovery, nanocarrier‐mediated hepatoprotective administration and precision medicine strategies for the prevention of drug‐induced liver injury (DILI). The intersection of antimony‐ and NSAID‐induced damage at a limited number of druggable targets supports the use of multi‐target natural therapies as logical complements to traditional hepatoprotection. However, the strength of evidence supporting this convergence is heterogeneous: Several downstream mechanisms—particularly NLRP3 inflammasome activation, ferroptosis, pyroptosis and necroptosis in antimony‐induced hepatotoxicity—are supported mainly by in vitro and animal data rather than confirmed human evidence, and are treated in this review as emerging or hypothetical rather than established. As this is a narrative rather than a systematic review, the literature search strategy, evidence‐grading approach and limitations are described explicitly to aid transparent interpretation.